Fundamental aspects of the biology of human immunodeficiency virus (HIV) infection, such as the anatomical location of ongoing viral replication during potent antiretroviral therapy, remain undefined. Evaluating pathophysiological questions during HIV disease is hampered by techniques that are too invasive to perform on human subjects. Investigations must therefore rely on laboratory based ex vivo experiments, autopsy specimens, or animal models that are plagued with potential artifacts that obscure extrapolation of results to natural infection. Positron emission tomography (PET) technology, however, may provide a powerful and safe technique to study the pathogenesis of HIV disease in vivo. Specifically, PET may be able to non-invasively detect HIV infection and localize tissues of active viral replication. This pilot study was designed to establish our ability to employ PET imaging as a marker of HIV infection in healthy HIV-infected subjects and to evaluate the impact of disease stage on PET scan pattern.Our preliminary results indicate that PET scans of healthy HIV-infected patients clearly differ from images of HIV-uninfected controls. In particular, scans of patients with high viral burdens (>50,000 copies/ml) and relatively preserved immune systems (T-cell counts > 200 cells/microliter) demonstrate abnormal PET signal in multiple lymph node chains, a finding not seen in any of the uninfected controls. This pattern may reflect areas of active viral replication, given that scans of patients treated with potent antiretrovirals (that suppress their virus to below the level of detectability) do not demonstrate PET abnormalities in their lymph nodes and are similar to images of uninfected controls. Future scans will be of healthy HIV-infected patients with more advanced immune system destruction (T-cells < 50 cells/microliter) so that we will be able to evaluate the impact of disease stage on PET scan pattern.